The synthesis of chemical compounds designed to selectively sensitize hypoxic cells in some tumors to the lethal effect of radiation has been the focus (See for example (a) K. C. Agrawal et al., J. Med. Chem., 22, 583 (1979); (b) J. F. Fowler et al., Cancer Treat. Rev., 3, 227 (1976); and (c) G. E. Adams et al., Nature (London) 239, 23 (1972).) of much research effort over the past several years. It has been observed that the ability of the radiosensitizing drugs to sensitize hypoxic cells is directly related to the electron affinity of the molecule. G. E. Adams and coworkers recently completed an impressive study of radiosensitization in hypoxic Chinese hamster cells in vitro by a series of nitroaromatic and nitroheterocyclic compounds (see, G. E. Adams et al., Int. J. Radiat. Biol., 35, 133 (1979)). Among the conclusions they reached was the overwhelming importance of reduction potential to radiosensitization efficiency and the insensitivity to other, non-redox properties. The study also noted a failure to demonstrate any influence of solvent partition properties on radiosensitization efficiency or aerobic cytotoxicity of the compounds. For example, a 2-nitroimidazole, a 5-nitrofuran, a nitrobenzene and a quinone having virtually the same reduction potential were confirmed to have similar aerobic cytotoxicities. This lack of sensitivity to changes in molecular structure other than those which influence redox properties offers, according to the authors, an extraordinary flexibility in drug design. The most widely used radiosensitizers are the nitro derivatives, especially metronidazole and misonidazole. (See J. Martin Brown, Radiat. Res. 70, 469 (1977); G. E. Adams, Int. J. Radiat. Oncol. Biol. Phys., 4, 135 (1978); and J. Denekamp and J. F. Fowler, Int. J. Radiat. Oncol. Biol. Phys., 4, 168 (1978).) Some of these nitro compounds have already been used in radiochemical treatment of human subjects. However, recent investigations show that gastrointestinal toxicity with metronidazole and neurotoxicity with misonidazole limits the dosage of drug that can be administered. Some investigations claim that toxicity of the nitro derivatives arises when they are reduced to amines in the metabolic process.
The primary object of the present invention is to provide a new class of radiosensitizing agents which do not possess nitro groups.
It is a further object of the present invention to provide a new process for synthesizing the radiosensitizers of the present invention, namely, 2H-isoindolediones.
These and other objects will become more apparent from the discussion which follows.